Expert Commentary Intrinsic Fibrinolysis and Arterial Thrombosis

Inherited disorders of coagulation predispose pa-tients to thromboembolic events, the majority of which occur in the venous circulation.1 However, disorders of the endogenous fibrinolytic system are more closely associated with arterial throm-bosis, particularly in subjects with underlying ath-erosclerotic disease. Reduced fibrinolysis in these subjects results in formation of thrombus on un-derlying atherosclerotic plaque, occluding the vessel lumen and reducing distal arterial flow. This in turn leads to clinical events such as my-ocardial infarction as well as progression of ath-erosclerotic disease to more severe levels.1 The endogenous fibrinolytic system is the system by which the body lyses excess or inap-propriately formed thrombus. Spontaneous lysis of blood clots was first described by Denys2 in 1889; the phenomenon was termed "fibrinolysis" by Dastre3 in 1893. It is now known that fibri-nolysis occurs when the enzyme plasmin lyses fibrin clots.4 Plasmin, a serine protease, is pre-sent in serum primarily as the inactive proen-zyme plasminogen. Cleavage of plasminogen to plasmin occurs via the plasminogen activators tissue-type plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA). Tissue-type plasminogen activator is more-im-portant as an anticoagulant enzyme, while uPA is more important in tissue remodeling.5 Inhibition of fibrinolysis occurs at two levels, by the action of alpha-2-antiplasmin on plasmin, and via inhi-bition of tPA activity by plasminogen activator inhibitor 1 (PAI-1). PAl-i forms a one-to-one sto-ichiometric complex with tPA, which results in inhibition; only free, nonbound tPA is biological-ly active4 (Figure 1)